Antineoplastic antibiotics in the combined chemotherapy of squamous cell carcinoma

Sixty five patients with squamous cell carcinoma of various localization at stages III-IV or with severe relapses were subjected to chemotherapy according to 3 schemes: AMB (adriamycin + methotrexate + bleomycin or bleomycetin), 34 patients; AMBP (adriamycin + methotrexate + bleomycetin + platidiam), 17 patients and AMFP (adriamycin + methotrexate + fluorofur + platidiam), 14 patients. The efficacy of the schemes was 35, 17.7 and 43 per cent respectively. The AMB scheme in treatment of the patients with maxillofacial carcinoma resulted in remission in 8 out of 20 cases (40 per cent). Analysis of the adverse reactions to the chemotherapy showed that all the three schemes were relatively low toxic. The AMB and AMFP schemes may be recommended for treatment of patients with disseminated or inoperable forms of epidermoid tumors in oncological departments.     

Experience with using carminomycin in oncological clinical practice]

Carminomycin is an original antitumor antibiotic from the anthracycline group isolated at the Institute of New Antibiotics (USSR) in 1973. Pharmacological investigation of carminomycin revealed its satisfactory absorption from the gastrointestinal tract which proved to be a distinguishing property of the antibiotic as compared to other anthracyclines such as adriamycin and rubomycin. The clinical trials of carminomycin showed that it was mainly active against soft tissue sarcoma and breast cancer, lymphosarcoma, neuroblastoma, Wilms' tumor and Ewing's sarcoma in children, as well as acute leukemia. Various regimens for the antibiotic administration were applied: short-term, single and long-term. Suppression of hemopoiesis was considered as a limiting toxic effect. By the data available carminomycin had lower cardiotoxicity as compared with rubomycin and adriamycin. Development of oral carminomycin is believed promising.     

New concepts of microsomal metabolism of the antibiotic adriamycin

Experimental and literary data are presented which are at variance with the known conception of adriamycin (AD) shunting the chain of microsomal electron transfer. AD, carminomycin, rubomycin, mitomycin C, and coenzyme Q9 are shown to interact with NADPH, in the absence of enzymes, with the nucleotide oxidation. A new scheme of AD metabolism is suggested, according to which AD in the hydroquinone form enters the chain of electron transfer in microsomes between NADPH and flavoprotein.     

Formation of free radicals during interaction of adriamycin and carminomycin with xanthine oxidase

Xanthine oxidase reduces carminomycin and adriamycin to the semiquinones which have been detected by ESR technique. The steady state carminomycin semiquinone concentration is some tens times higher than the corresponding value for adriamycin. This effect appears to be a result of carminomycin semiquinone stabilization due to internal hydrogen bonding.     

Effect of the anthracycline group antibiotics, mitomycin C and bruneomycin, on the transduction of drug resistance in staphylococci]

The effect of various concentrations of antitumor antibiotics, such as carminomycin, rubomycin, adriamycin, mitomycin C and bruneomycin on transduction of erythromycin resistance from the donor strain 8325 P II/de of Staph, aureus to the recipient strain 8325-I in different transduction systems was studied. It was shown that the above antibiotics inhibited the transduction in the systems with constant presence of the drugs. Preliminary treatment of the recipient cells with the drugs in the subbacteriostatic doses did not decrease the transfer frequency. The preliminary treatment of the donor cells resulted in an increase in the phase titer and the transfer frequency in the "preliminary-treated donor + recipient" system.     

Inhibition of synthesis of nucleic acids, proteins and respiration in isolated thymocytes by anthracyclines

The effect of anthracycline antibiotics such as carminomycin, daunomycin (rubomycin) and adriamycin on respiration and synthesis of nucleic acids and protein was studied comparatively. The anthracyclines inhibited the processes. By their efficacy in that respect they could be arranged in the following order: carminomycin greater than rubomycin greater than adriamycin. Thus, 50 per cent inhibition of nucleic acid synthesis in the thymocytes required 0.027, 0.044 and 0,173 mM of carminomycin, rubomycin and adriamycin respectively. Protein synthesis and respiration in the thymocytes were less sensitive to the effect of the anthracyclines than synthesis of nucleic acids. The study results were compared with the literature data on the effect of the compounds on respiration and synthesis of nucleic acids and protein in tumour and bacterial cells.     

Effect of rubomycin, carminomycin and adriamycin on respiration in liver mitochondria in various metabolic states, respiratory control and ADP/O ratio

A comparative study on the effects of antitumour antibiotics of the anthracycline group (rubomycin, carminomycin and adriamycin) on respiration and oxidative phosphorylation in liver mitochondria in various metabolic states has been carried out for the first time. It was shown that the antibiotics under study cause partial inhibition of mitochondrial state 3 respiration, which is eliminated by an uncoupler. Treatment of liver mitochondria with the antibiotics decreases the ADP/O and respiratory control values and stimulates state 4 respiration. The latter is partly inhibited by oligomycin. The uncoupled respiration is decelerated in the presence of the antibiotics. Under these conditions the oxidation of succinate is inhibited by lower concentrations of the antibiotics than that of NAD+-dependent substrates. It was shown that the maximal activity is exerted by the most polar agent carminomycin, while the hydrophobic rubomycin is the least active. The experimental results are discussed in terms of the toxic effect of antitumour antibiotics.     

Action of carminomycin on leukemic cell proliferation and some problems of its use in the combined therapy of leukemias

The effect of carminomycin on the mitotic cycle of the cells of the transplantable leukemia L-1210 and the therapeutic activity of other antitumor drugs, such as phopurine and cyclophosphane was studied on mice BDF1. It was found that the cells in phases S and G2 of the mitotic cycle were most sensitive to carminomycin. Transfer G1--S and phase G1 were characterized by resistance to the antibiotic effect. When carminomycin was used in combination with phopurine or cyclophosphane, clear dependence of the therapeutic efficacy on the treatment scheme was noted. Simultaneous administration of all the three drugs resulted in potentiation of the antileukemic effect. An analogous effect was observed when carminomycin was administered prior to phopurine or cyclophosphane. When the order of the drugs use was reverse, the efficacy of the combined therapy was significantly lower than the summation antileukemic effect of the drugs.     

Comparison of the antitumor, immunodepressive and toxic properties of carminomycin-albumin complexes differing in carminomycin content

Bovine serum albumin (BSA) and carminomycin, an anthracycline antibiotic, were subjected to conjugation with glutaraldehyde and their complexes with various contents of the antibiotic were prepared. The molar ratios of carminomycin and BSA were 8:1, 4:1, and 2:1. The antitumor effect of the preparations was studied on the models of mouse transplantable lymphosarcoma LIO equal 1 and ascitic forms of mouse lymphadenosis NK/Ly in vivo and in vitro. Their immunodepressant effect was evaluated from the decrease in the hemagglutinin titers in the mice immunized with sheep red blood cells. It was shown that when the toxicity of the complexes was the same, their antitumor and immunodepressant activities were different. The therapeutic activity of carminomycin in the four- and eight-substituted complexes was much higher than that of carminomycin alone. It is suggested that the differences in the activity of the complexes were connected with differences in their pharmacokinetics. It was found that the chemotherapeutic properties of the complexes may have changed by variation of the number of the cytostatic residues in the albumin molecule. The findings indicate that the whole complex molecule interacts with the malignant cell and not carminomycin preliminarily detached from it.     

An Unusual Nad(P)H-Dependent Oi-Generating Redox System in Hepatoma 22a Nuclei

Nuclear membranes from many tumors contain an unusual redox chain discovered originally in the Hepatoma 22a nuclear membranes⁷ which catalyzes superoxide dismutase-sensitive adrenaline oxidation to adrenochrome in the presence of either NADPH or NADH as electron donor, the reaction being inhibited by cyanide and azide. This redox chain can reduce anthracycline antitumor antibiotics adriamycin and carminomycin to their free radical states under anaerobic conditions. Evidence has been obtained for a higher stability of the carminomycin radical as compared to that of adriamycin. Operation of the nuclear membrane-bound redox chain can be a source of oxygen radical-mediated single strand breaks in DNA. The role of the nuclear membrane-associated electron transfer chain in augmenting the anticancer action of the anthracycline antibiotics is discussed.     

Melatonin controls oxidative stress and modulates iron, ferritin, and transferrin levels in adriamycin treated rats

AIM: Chemotherapy with adriamycin (ADR) is limited by its iron-mediated pro-oxidant toxicity. Because melatonin (MLT) is a broad spectrum antioxidant, we investigated the ability of MLT to control iron, its binding proteins, and the oxidative damage induced by ADR. MAIN METHODS: ADR was given as single i.p. dose of 10 mg kg(-1) body weight into male rats. MLT at a dose of 15 mg kg(-1) was injected daily for 5 days before ADR treatment followed by another injection for 5 days. Biochemical methods were used for this investigation. KEY FINDINGS: ADR injection caused elevations in plasma creatine kinase isoenzyme, lactic dehydrogenase, and aminotransferases, iron, ferritin, and transferrin. These changes were associated with increases in lipid peroxidation and protein oxidation as well as decreases in glutathione (GSH) levels and glutathione-S-transferase (GST) activity, while glutathione peroxidase (GSH-Px), and catalase (CAT) activity were elevated in the heart and liver of ADR treated rats. In the MLT+ADR group, the cardiac and hepatic function parameters and the levels of iron, transferrin and ferritin in plasma were normalized to control levels. The rats that were subjected to MLT+ADR had normalized CAT and GSH-Px activity and decreased TBARS and protein carbonyl levels compared the group only treated with ADR. GST activity and GSH concentration in the heart and liver were normalized when MLT accompanied ADR treatment. SIGNIFICANCE: MLT ameliorated oxidative stress by controlling iron, and binding protein levels in ADR treated rats demonstrating the usefulness of adriamycin in cancer chemotherapy and allowing a better management of iron levels.     

An Unusual Nad(P)H-Dependent Oi-Generating Redox System in Hepatoma 22a Nuclei

Nuclear membranes from many tumors contain an unusual redox chain discovered originally in the Hepatoma 22a nuclear membranes⁷ which catalyzes superoxide dismutase-sensitive adrenaline oxidation to adrenochrome in the presence of either NADPH or NADH as electron donor, the reaction being inhibited by cyanide and azide. This redox chain can reduce anthracycline antitumor antibiotics adriamycin and carminomycin to their free radical states under anaerobic conditions. Evidence has been obtained for a higher stability of the carminomycin radical as compared to that of adriamycin. Operation of the nuclear membrane-bound redox chain can be a source of oxygen radical-mediated single strand breaks in DNA. The role of the nuclear membrane-associated electron transfer chain in augmenting the anticancer action of the anthracycline antibiotics is discussed.     

Antitumor antibiotics in the treatment of nephroblastomas in children

The results of the chemotherapy of 20 children with nephroblastoma are analysed. The patients were treated according to the following scheme: vincristine in a dose of 0.05 mg kg bw once a week on the 1st, 8th, 15th and 22nd days, dactinomycin in a dose of 15 micrograms/kg once a day for 3 days on the 1st, 2nd and 3rd days of adriamycin in a dose of 30-40 mg/m2 on the 15th day of the treatment course. The postoperative chemotherapy was started 10 days after the operation. It was performed in 4 courses with intervals of 3 weeks. The efficacy of the treatment was estimated with angiography, echography and computer-aided tomography. The above scheme proved to be efficient in the treatment of the children with nephroblastoma. Reliable control of the tumor size during the preoperative treatment was shown to be possible.     

Comparative study of the cytotoxic effects of anthracycline antibiotics on heterotransplants of human breast cancer cultivated in diffusion chambers in vivo

Cytotoxic activity of doxorubicin, daunomycin, carminomycin and ruboxyl against 50 human breast cancer heterotransplants in diffusion chambers was studied. The effect was estimated autoradiographically on the 6th or the 7th day of the cultivation after the drug administration in the maximum tolerance doses. The tumors were considered sensitive when the labeling index of their transplants after the treatment appeared to be reduced by 50 or less per cent against the control. The number of the tumors sensitive to all the drugs amounted to 72-80 per cent. 19 tumors were sensitive to 4 antibiotics. 14 and 8 tumors were sensitive to 3 and 2 antibiotics, respectively, and only 1 tumor was sensitive to 1 drug. The sensitivity significantly correlated with the initial labeling index of the primary tumors and their heterotransplants. The results suggested that daunomycin and ruboxyl possessed a high cytotoxic activity close to that of doxorubicin and carminomycin and might be recommended for clinical trials in the treatment of patients with breast cancer.     

Effect of the molecular structure of natural anthracycline antibiotics on their relative hydrophobicity

Relative hydrophobicities of anthracycline antibiotics, adriamycin, rubomycin and carminomycin, have been measured by the two-phase distribution method. Two different biphasic systems were used for this purpose. Possible reasons of discrepancies between results obtained and other authors, data are discussed. It was established that the relative hydrophobicities of the compounds investigated contradict the theory of increment additivity. The results are compared with quantum-chemical calculations.     

In vivo enhancement of chemotherapy with static electric or magnetic fields

We evaluated the ability of both static electric and static magnetic fields to enhance the in vivo action of a chemotherapeutic agent, adriamycin, against transplanted mammary tumors in mice. Female B6C3F1 mice with transplanted mammary adenocarcinoma were divided into four randomized groups and injected with 10 mg/kg adriamycin on day 7 of the study. Three of the groups were then exposed to nonuniform static electric or static magnetic fields. The resulting tumor regression in each group was measured four times during the remaining 13 days of the 20 day study. Two-sided statistical tests revealed all of the static field exposed groups achieved significantly greater (P 相似文献   

Use of 5-fluorouracil, bleomycetin and platidiam in combined treatment of localized cancer of the larynx]

Preliminary results of chemoradiotherapy in 30 patients with the larynx cancer T3T4N0M0 are presented. Two treatment schemes were applied. According to scheme I, the treatment was started with chemotherapy with 5-fluorouracil in doses of 1000 mg on days 1, 2 and 3, bleomycetin in doses of 15 mg on days 1, 2 and 3 and platidiam in doses of 120 mg/m2 on day 4 followed by radiotherapy to the total dose of 66 to 70 Gy. Scheme II included two analogous courses of the chemotherapy, one prior to the radiotherapy and the other after irradiation in a dose of 38 to 40 Gy, after a two-week interval the radiotherapy was continued to doses of 66 to 70 Gy. 15 patients were treated in accordance with each scheme. Complete resorption of the tumor was observed in 66.6 and 83.3 per cent of the patients treated according to schemes I and II, respectively. The results showed that the use of 5-fluorouracil, bleomycetin and platidiam in combination with radiotherapy was promising in treatment of patients with local cancer of the larynx.     

Adriamycin in the combined chemotherapy of small-cell lung cancer

The results of combined chemotherapy and chemoradiotherapy of 158 patients with small cell lung cancer are presented. Adriamycin was used as one of the components of the induction chemotherapy of 98 out of the 158 patients. Chemoradiotherapy (nitrosomethylurea, methotrexate, CCNU, adriamycin, vincristine, DTIC, radiotherapy) was performed according to 4 schemes and combined chemotherapy (cyclophosphamide, adriamycin, methotrexate, or CCNU, cyclophosphamide, methotrexate plus adriamycin, vincristine, natulan) was performed according to 2 schemes. The total efficacy (complete and partial regression) of the 6 schemes averaged to 80 per cent. The number of patients with complete regression amounted to 29 per cent. Long-term survival for more than 2 years was observed in 17 per cent of the patients. No signs of metastases or relapses for 5 years were recorded in 6 per cent of patients. Adriamycin is one of the most active antitumor drugs in combined chemotherapy and chemoradiotherapy of small cell lung cancer.     

Carminomycin study in breast cancer]

Karminomycin was used for the treatment of cases with disseminated cancer of the mammary gland in doses of 5 mg/m2 of the body surface intravenously every day for 5 days (15 patients) or 6 mg/m2 twice a week for 2-3 weeks (30 patients). Partial remission or diminution of the tumor size at least by 50 per cent was observed in 26 and 17 per cent of the patients respectively. The remission duration was from 2 to 6 months. With the use of the shortperiod scheme the frequency of the direct side reactions increased. Leucopenia as a side effect was registered in 100 and 40 per cent of the patients and thrombocytopenia was registered in 18 and 3 per cent of the cases respectively.     

CA 15.3 as a tumour marker in breast cancer

CA 15.3 is an antigenic determinant associated with human mammary carcinomas. Two murine monoclonal antibodies have been raised against the determinants, and an immunoradiometric assay (IRMA-Kit, Centocor, USA) has been developed to determine the antigen levels in plasma of cancer patients. Based on the 99% confidence limit of healthy women, plasma values above 30 U/ml are considered abnormal. Plasma samples from 357 women were examined in the present study. Healthy females (n = 84) ranged below the cut-off level between less than 10 and 29 U/ml. Higher values were found in 12.5% of benign breast diseases and in 23.6% of breast cancer patients, including all stages. Depending on the stage of the disease, there were elevated levels in 11% of operable breast cancer patients preoperatively, in 7% of the cases with no evidence of disease after primary treatment and in 63.5% of patients with disseminated mammary carcinoma. In metastasized breast cancer the frequency and the degree of abnormal titers were closely related to the extent of the metastatic disease. Follow-up examinations of 63 patients under cytotoxic therapy showed CA 15.3 changes correlating well with the clinical course in up to 90% of the antigen positive cases. The present data indicate that CA 15.3 may be useful in the surveillance of breast cancer patients. However in our study one third of the patients with metastatic breast cancer did not show any increase in CA 15.3 and must be regarded as antigen negative.